PROJECT SUMMARY This proposal describes a five-year training program for development of a career in clinical research focused on fetal predictors of neurodevelopmental (ND) outcome in critical congenital heart disease (CHD). The candidate has training in pediatric and fetal cardiology. The goals of this award are to rigorously conduct this research proposal, to use the training obtained to develop into a mentor to other trainees and junior faculty and to use this award as a vehicle to become a federally funded independent investigator. To achieve these goals, the applicant has set up a training plan that will include mentoring, course work, hands-on conduct of research and didactic educational activities. This project will be carried out under the mentorship of Patrick McQuillen, MD, a leader in neurodevelopmental outcomes of children with CHD. Complementary mentorship will be provided by Drs. Donna Ferriero and Jim Barkovich, experts in establishing correlations between brain imaging and neurologic outcomes. This mentoring team has successfully mentored students, fellows and junior faculty, including K-level awards. An advisory committee has been assembled to help guide the candidate's career development. This application focuses on understanding the regulation of cerebral blood flow and oxygenation in fetuses with critical CHD as compared to a normal comparative group. Furthermore, the protocol aims to identify the link between fetal cerebral regulation and adaptation with postnatal structural and functional neurologic outcomes in patients with transposition of the great arteries (TGA) and hypoplastic left heart syndrome (HLHS), two common yet physiologically distinct cardiac lesions. Literature demonstrates that these patients have evidence of delayed brain development in late gestation and at birth and are vulnerable to peri- operative white matter injury. The etiology of these findings is likely related to abnormalities in cerebral oxygen delivery as a result of CHD, which may be secondary to decreased cerebral perfusion, decreased blood oxygen content, changes in metabolism or a combination of all. The first part of this proposal focuses on the prenatal time period. We plan to demonstrate differences in regulation of cerebral blood flow (as measured by trans-cranial Doppler) and oxygenation (as measured by T2* MRI) in CHD fetuses as compared to normal fetuses by utilizing brief administration of maternal hyperoxia to acutely alter physiology. To achieve this, we plan to perform a cross-sectional study comparing these measures between CHD and normal fetuses. The second component of this proposal extends to the postnatal time period and aims to understand the relationship between fetal cerebral regulation and postnatal brain structure (MRI at birth) and function (ND outcome at 12 months) in CHD. To achieve this, we plan to conduct a prospective cohort study of fetuses with TGA and HLHS to assess this relationship and to assess differences by cardiac lesion. This proposal will identify fetal physiologic effects on ND outcome in fetuses with CHD, providing critical information to set up future intervention studies with an eventual goal of improving ND outcomes in children with complex CHD.